Preparation method of 5-(aminomethyl) benzene-1, 3-diacid dimethyl ester

Abstract

The invention belongs to the field of organic matter synthesis, and discloses a preparation method of 5-(aminomethyl) benzene-1, 3-diacid dimethyl ester, which comprises the following steps: (1) stirring 5-(bromomethyl) dimethyl isophthalate and phthalimide potassium salt in an organic solvent to react for 10-14 hours, after the reaction is monitored by an LCMS (Liquid Chromatography Mass Spectrometer), adding the reaction liquid into water, and after the reaction is finished, filtering and drying to obtain 5-(aminomethyl) benzene-1, 3-diacid dimethyl ester; separating out a white solid, filtering and drying to obtain 5-((1, 3-dioxoisoindoline-2-yl) methyl) dimethyl isophthalate; and (2) mixing the 5-((1, 3-dioxoisoindoline-2-yl) methyl) dimethyl isophthalate obtained in the step (1) with hydrazine hydrate in an organic solvent, reacting at 35-45 DEG C for 2-4 hours, after the reaction is monitored by an LCMS (Liquid Chromatography Mass Spectrometer), extracting the reaction liquid for three times by adopting an extracting solution, merging organic phases collected by the three times of extraction, washing the organic phases for three times, and drying to obtain a white solid, namely the 5-((1, 3-dioxoisoindoline-2-yl) methyl) dimethyl isophthalate. And adding petroleum ether, pulping, and filtering to obtain the product dimethyl 5-(aminomethyl) benzene-1, 3-diacid. The preparation method provided by the invention is simple in operation steps, high in product yield, low in byproduct content, safe and efficient.

Description

Technical Field

[0001] The invention relates to the field of organic synthesis, and more specifically to a method for preparing 5-(aminomethyl)benzene-1,3-dioic acid dimethyl ester. Background Art

[0002] Dimethyl 5-(aminomethyl)benzene-1,3-dicarboxylate is mainly used as an organic synthesis intermediate, especially in the synthesis of dyes and pigments, and can also be used as a pharmaceutical intermediate. Therefore, studying its preparation method has important significance and application value.

[0003] At present, the conventional method for preparing 5-(aminomethyl)benzene-1,3-dioic acid dimethyl ester is to use 5-(bromomethyl)isophthalic acid dimethyl ester as the starting material, stir sodium azide in N,N-dimethylformamide to form 5-(azidomethyl)isophthalic acid dimethyl ester, and then use palladium carbon for hydrogenation. However, the use of sodium azide is very dangerous, and the use of palladium carbon will also incur high costs. Therefore, a safe, efficient and low-cost method for preparing 5-(aminomethyl)benzene-1,3-dioic acid dimethyl ester is urgently needed. Summary of the invention

[0004] In order to solve the problems in the prior art, the present invention aims to provide a method for preparing dimethyl 5-(aminomethyl)benzene-1,3-dioate. The preparation method provided by the present invention has simple operation steps, high product yield, low by-product content, and is safe and efficient.

[0005] In order to achieve the purpose of the invention, the present invention adopts the following technical solutions:

[0006] The present invention provides a method for preparing 5-(aminomethyl)benzene-1,3-dioic acid dimethyl ester, which comprises the following steps:

[0007] (1) 5-(bromomethyl)dimethyl isophthalate and potassium phthalimide are stirred in an organic solvent for reaction for 10 to 14 hours. After the reaction is completed as monitored by LCMS, the reaction solution is added to water to precipitate a white solid, which is filtered and dried to obtain 5-((1,3-dioxoisoindolin-2-yl)methyl)dimethyl isophthalate;

[0008] (2) Mixing the 5-((1,3-dioxoisoindolin-2-yl)methyl)isophthalic acid dimethyl ester obtained in step (1) with hydrazine hydrate in an organic solvent, reacting at 35-45° C. for 2-4 hours, and after the reaction is completed as monitored by LCMS, extracting the reaction solution three times with an extracting liquid, combining the organic phases collected from the three extractions, washing the organic phase three times with water, and drying to obtain a white solid, adding petroleum ether to pulp, and filtering to obtain the product 5-(aminomethyl)benzene-1,3-dioic acid dimethyl ester.

[0009] As a preferred technical solution, the organic solvent in step (1) is N,N-dimethylformamide.

[0010] As a preferred technical solution, the mass volume ratio of 5-(bromomethyl)dimethyl isophthalate and the organic solvent in step (1) is 1 g: 5 to 15 mL.

[0011] As a preferred technical solution, the mass volume ratio of 5-(bromomethyl)dimethyl isophthalate and the organic solvent in step (1) is 1 g:10 mL.

[0012] As a preferred technical solution, the mass ratio of 5-(bromomethyl)dimethyl isophthalate and potassium phthalimide in step (1) is (40-60):(30-40).

[0013] As a preferred technical solution, the mass ratio of 5-(bromomethyl)dimethyl isophthalate and potassium phthalimide in step (1) is 50:35.5.

[0014] As a preferred technical solution, the volume ratio of the reaction solution to water in step (1) is 1:(4-5).

[0015] As a preferred technical solution, the mass ratio of dimethyl 5-((1,3-dioxoisoindolin-2-yl)methyl)isophthalate and hydrazine hydrate in step (2) is (50-70):(20-30).

[0016] By adopting the above technical scheme, under the ratio of 5-((1,3-dioxoisoindolin-2-yl)methyl)isophthalic acid dimethyl ester and hydrazine hydrate of (50-70):(20-30), 5-((1,3-dioxoisoindolin-2-yl)methyl)isophthalic acid dimethyl ester and hydrazine hydrate can fully react to obtain 5-(aminomethyl)benzene-1,3-dioic acid dimethyl ester with higher yield. If the feeding amount of hydrazine hydrate is further increased, although it is beneficial to the full consumption of 5-((1,3-dioxoisoindolin-2-yl)methyl)isophthalic acid dimethyl ester, the yield of 5-(aminomethyl)benzene-1,3-dioic acid dimethyl ester is not significantly improved, and a byproduct (5-(aminomethyl)isophthalic acid dihydrazide) of aminoester exchange between hydrazine hydrate and substrate lipid group will appear.

[0017] As a preferred technical solution, the organic solvent in step (2) is methanol.

[0018] As a preferred technical solution, the mass volume ratio of dimethyl 5-((1,3-dioxoisoindolin-2-yl)methyl)isophthalate and the organic solvent in step (2) is 1 g:15-20 mL.

[0019] As a preferred technical solution, the mass volume ratio of dimethyl 5-((1,3-dioxoisoindolin-2-yl)methyl)isophthalate and the organic solvent in step (2) is 1 g:17 mL.

[0020] As a preferred technical solution, the extract in step (2) is a mixture of water and dichloromethane, and the volume ratio of water to dichloromethane is 3:(1-2).

[0021] As a preferred technical solution, the yield of 5-(aminomethyl)benzene-1,3-dioic acid dimethyl ester obtained in step (2) is 80% to 85%.

[0022] Beneficial Effects

[0023] 1. The present application firstly reacts 5-(bromomethyl) dimethyl isophthalate and potassium phthalimide with a solvent for nucleophilic substitution reaction, and then reacts with hydrazine hydrate for hydrazinolysis reaction, so as to obtain the target product with a higher yield;

[0024] 2. This application further optimizes the feed ratio and conditions of the reduction reaction, thereby increasing the conversion rate of the reaction raw materials, and the yield of the main product is 80-85%, and the product is relatively single, which is easy to carry out post-processing operations;

[0025] 3. The method of the present invention for synthesizing 5-(aminomethyl)benzene-1,3-dioic acid dimethyl ester has simple operation steps, low by-product content, and is safe and efficient, and can realize industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0026] Figure 1 This is a reaction equation diagram for Example 1 of the present application.

[0027] Figure 2 This is the NMR spectrum of 5-(aminomethyl)benzene-1,3-dioic acid dimethyl ester obtained in Example 1 of the present application.

[0028] Figure 3 This is the reaction equation diagram of Comparative Example 6 of the present application.

[0029] Figure 4 This is the reaction equation diagram of Comparative Example 7 of the present application. DETAILED DESCRIPTION

[0030] The experimental methods in the following examples of the present invention, where no specific conditions are specified, are usually carried out under conventional conditions or under conditions recommended by the manufacturers. The various commonly used chemical reagents used in the examples are all commercially available products.

[0031] The following will be combined with the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0032] The experimental materials used in the embodiments and comparative examples of the present invention are as follows:

[0033] (1) 5-(bromomethyl)dimethyl isophthalate: from Shanghai Titan Technology Co., Ltd.;

[0034] (2) Potassium phthalimide: from Shanghai Titan Technology Co., Ltd.;

[0035] (3) Hydrazine hydrate: from Shanghai Titan Technology Co., Ltd.;

[0036] (4) N,N-dimethylformamide: from Shanghai Titan Technology Co., Ltd.;

[0037] (5) Methanol: Sourced from Shanghai Titan Technology Co., Ltd.

[0038] Testing equipment:

[0039] LCMS is a liquid chromatography-mass spectrometry detection method. The liquid chromatography-mass spectrometry instrument used in the present invention is an instrument of model LCMS-2020 manufactured by Shimadzu Instruments Co., Ltd. of Japan.

[0040] Example 1

[0041] This embodiment specifically provides a method for preparing 5-(aminomethyl)benzene-1,3-dioic acid dimethyl ester and its preparation method, and the specific steps are as follows:

[0042] (1) Dissolve 50 g (1.0 eq) of 5-(bromomethyl)isophthalic acid dimethyl ester and 35.5 g (1.1 eq) of potassium phthalimide in 500 mL of N,N-dimethylformamide and stir for 12 hours. LCMS monitors the completion of the reaction of 5-(bromomethyl)isophthalic acid dimethyl ester. Pour the reaction solution into 2000 mL of water to precipitate a white solid. Filter and dry to obtain 60 g of a white solid, which is directly used in the next step.

[0043] (2) 60 g of the white solid product obtained in step (1) was dissolved in 1000 mL of methanol, 25 g (3.0 eq) of hydrazine hydrate (mass fraction 80%) was added and reacted at 40° C. for 2 h. After the reaction was completed by LCMS monitoring, the mother liquor was poured into 1500 mL of water, extracted three times with 800 mL of dichloromethane, and the organic phases collected from the three extractions were combined, the organic phase was washed three times with water, and dried to obtain a white solid. 500 mL of petroleum ether was added for pulping, and 31 g of the target product 5-(aminomethyl)benzene-1,3-dioic acid dimethyl ester was obtained by filtration, with a yield of 83%.

[0044] The NMR spectrum readings of the target product were 1H NMR (400 MHz, DMSO) δ8.33 (s, 1H), 8.20 (s, 2H), 3.89 (s, 6H), 3.85 (s, 2H), 2.07 (s, 2H).

[0045] Comparative Example 1

[0046] The difference from Example 1 is that the reaction temperature in step (2) is room temperature and the reaction time is 16 hours. LCMS monitoring shows that the raw material reacts to 18%, and further extending the reaction time shows that the raw material reacts to 30% and no longer increases.

[0047] Comparative Example 2

[0048] The difference from Example 1 is that the equivalent of hydrazine hydrate in step (2) is 6 eq, and the reaction time is 16 h. LCMS monitoring shows that the raw material reacts to 40%, and the reaction time is increased to 24 h, and it is found that the raw material reacts to about 50%. The reaction degree of the raw material increases very slowly, and a byproduct (5-(aminomethyl)isophthalic acid hydrazide) of aminoester exchange between hydrazine hydrate and substrate lipid groups begins to appear.

[0049] Comparative Example 3

[0050] The difference from Example 1 is that in step (2), 25 g (3.0 eq) of hydrazine hydrate (80%) was added and reacted at 40° C. for 2 h, then the reaction was stopped and the solvent was evaporated. The sample was found to be entirely the by-product 5-(aminomethyl)isophthalic acid hydrazide.

[0051] Comparative Example 4

[0052] The difference from Example 1 is that the reaction time of step (2) is 16 hours. The samples sent were found to be all by-product 5-(aminomethyl)isophthalic acid hydrazide.

[0053] Comparative Example 5

[0054] The difference from Example 1 is that the equivalent of hydrazine hydrate in step (2) is 12 eq, and the reaction time is 16 h. LCMS monitoring shows that the raw material reacts to 40%, and the reaction time is increased to 24 h, and it is found that the raw material reacts to about 55%. The reaction degree of the raw material increases very slowly, and a byproduct (5-(aminomethyl)isophthalic acid hydrazide) of aminoester exchange between hydrazine hydrate and substrate lipid groups begins to appear.

[0055] Comparative Example 6

[0056] This embodiment specifically provides a method for preparing 5-(aminomethyl)benzene-1,3-dioic acid dimethyl ester and its preparation method, and the specific steps are as follows:

[0057] 1 g (1.0 eq) of dimethyl 5-(bromomethyl)isophthalate and 0.45 g (1.1 eq) of tert-butyl carbamate were dissolved in 20 mL of acetonitrile, 0.56 g (0.5 eq) of tetrabutylammonium bromide and 1.48 g (2.0 eq) of potassium phosphate were added, and stirred for 12 hours. LCMS monitoring of the reaction revealed that no reaction occurred.

[0058] Comparative Example 7

[0059] This embodiment specifically provides a method for preparing 5-(aminomethyl)benzene-1,3-dioic acid dimethyl ester and its preparation method, and the specific steps are as follows:

[0060] 0.20 g (1.0 eq) of dimethyl 5-(bromomethyl)isophthalate and 0.14 g (1.1 eq) of diphenylamine were dissolved in 6 mL of toluene, and 0.45 g (2 eq) of cesium carbonate, 0.04 (0.1 eq) of 1,1'-binaphthyl-2,2'-bisdiphenylphosphine, and 0.016 g (0.1 eq) of palladium (II) acetate were added, and stirred at 100° C. for 12 hours. LCMS monitoring of the reaction revealed that no reaction occurred.

[0061] By comparing Example 1 with Comparative Examples 1-5, it can be seen that when the reaction temperature, reaction time and hydrazine hydrate feeding equivalent in the present invention are changed, the yield of the reaction decreases and the by-products increase. It can be seen that only by adopting the specific raw material components and process conditions of the present application can a high yield product be obtained.

[0062] By comparing Example 1 with Comparative Examples 6-7, it can be seen that when the reaction substrate in the present invention is changed, the reaction of Example 1 of the present application does not occur.

Claims

1. A method for preparing dimethyl 5-(aminomethyl)benzene-1,3-dioate, characterized in that: The preparation method comprises the following steps: (1) 5-(bromomethyl)dimethyl isophthalate and potassium phthalimide are stirred in an organic solvent for reaction for 10 to 14 hours. After the reaction is completed as monitored by LCMS, the reaction solution is added to water to precipitate a white solid, which is filtered and dried to obtain 5-((1,3-dioxoisoindolin-2-yl)methyl)dimethyl isophthalate; (2) Mixing the 5-((1,3-dioxoisoindolin-2-yl)methyl)isophthalic acid dimethyl ester obtained in step (1) with hydrazine hydrate in an organic solvent, reacting at 35-45° C. for 2-4 hours, and after the reaction is completed as monitored by LCMS, extracting the reaction solution three times with an extracting liquid, combining the organic phases collected from the three extractions, washing the organic phase three times with water, and drying to obtain a white solid, adding petroleum ether to pulp, and filtering to obtain the product 5-(aminomethyl)benzene-1,3-dioic acid dimethyl ester.

2. The method for preparing dimethyl 5-(aminomethyl)benzene-1,3-diacetate according to claim 1, characterized in that: In the step 1, the organic solvent is N,N-dimethylformamide.

3. A method for preparing dimethyl 5-(aminomethyl)benzene-1,3-diacetate according to claim 1 or 2, characterized in that: The mass volume ratio of 5-(bromomethyl)dimethyl isophthalate and the organic solvent in step (1) is 1 g: 5-15 mL.

4. The method for preparing dimethyl 5-(aminomethyl)benzene-1,3-dioate according to claim 1, characterized in that: The mass ratio of 5-(bromomethyl)dimethyl isophthalate to potassium phthalimide in step (1) is (40-60):(30-40).

5. The method for preparing dimethyl 5-(aminomethyl)benzene-1,3-dioate according to claim 1, characterized in that: The volume ratio of the reaction solution to water in step (1) is 1:(4-5).

6. The method for preparing dimethyl 5-(aminomethyl)benzene-1,3-diacetate according to claim 1, characterized in that: The mass ratio of dimethyl 5-((1,3-dioxoisoindolin-2-yl)methyl)isophthalate to hydrazine hydrate in step (2) is (50-70):(20-30).

7. The method for preparing dimethyl 5-(aminomethyl)benzene-1,3-dioate according to claim 1, characterized in that: The organic solvent in step (2) is methanol.

8. The method for preparing dimethyl 5-(aminomethyl)benzene-1,3-dioate according to claim 1 or 6, characterized in that: The mass volume ratio of dimethyl 5-((1,3-dioxoisoindolin-2-yl)methyl)isophthalate and the organic solvent in step (2) is 1 g:15-20 mL.

9. The method for preparing dimethyl 5-(aminomethyl)benzene-1,3-dioate according to claim 1, characterized in that: The extract in step (2) is a mixture of water and dichloromethane, and the volume ratio of water to dichloromethane is 3:(1-2).

10. The method for preparing dimethyl 5-(aminomethyl)benzene-1,3-dioate according to claim 6, characterized in that: The yield of 5-(aminomethyl)benzene-1,3-dioic acid dimethyl ester obtained in the step (2) is 80% to 85%.

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